And rarely, I lol when someone does something conceptually simple, but incredibly clever, and it makes me happy. I read an abstract, laugh, read the rest of the paper, laugh, clap, and laugh. Clever people make me happy 🙂

A while back, I talked about a cell line I use in the lab called ‘TZM-bl’. These cells express HIV-1 receptor (CD4), and co-receptors (CCR5 and CXCR4), and have one more really neat feature: they have been genetically modified so that their genome contains the HIV-2 promoter which drives the production of two reporter enzymes (one makes infected cells glow, one makes them turn blue, when given the right substrates).

If TZM-bl cells are infected with HIV-1, the HIV-1 Tat protein will go to the nucleus of the TZMs, ‘see’ the HIV-2 promoter, and say ‘YAY! THAT is where IM supposed to go! LA-LA-LA-LA-LA-LA!’. This drives the production of the reporter enzymes in infected cells.

Its a useful tool in the laboratory.

… Why dont we turn the concept into something that is useful in the clinic… ?
Long-time readers of ERV know that I am not at all impressed with the idea of gene therapy as a viable real-world therapy for HIV-1 infection/prevention. We could yank CCR5 off the surface of HIV-1 target cells (though its worked in transplant form, it could theoretically work in an artificial gene therapy form). We could force B-cells to express a SUPER AWESOME anti-HIV antibody (and pray there is nothing in the quasispecies that can escape, LOL).

But these folks had a really simple, really clever idea:

What if we, like, make T-cells that like, have an anti-HIV alarm system, or something? Like, when they get infected with HIV-1, that turns on something that kills HIV-1?

*blink*

*blink*

Yes… Assuming you could do that, what if you do that?

:-/

Im not being sarcastic! This idea is incredible in its simplicity!

They took the basics of TZM-bls (transcription of genes driven by the HIV-2 promoter, only works if Tat is there), and changed it a bit. Made cells with the HIV-1 promoter driving the transcription of a suicide gene from E. coli (!!!), mazF. mazF chops up RNA.

So when these genetically modified T-cells were infected with HIV-1, the Tat protein saw the artificial ‘HIV-1 promoter’, said ‘YAY! PROMOTER! YAY ME!’. Tat goes on to help make mazF:

The resulting induction of MazF expression leads to the cleavage of newly emerged HIV-1 mRNAs so that Tat protein synthesis is no longer sustainable. However, it is important to note that HIV-1 infection does not hamper cell growth and that the HIV-1 provirus genome is retained in the MazF-transduced cells. Therefore, the cellular level of Tat appears to be maintained at a very low level so that the level of MazF induction is also kept very low enough to cleave HIV-1 mRNAs, but not cellular mRNAs.

This only results in an infected cell making a tiny bit of mazF. Its not enough to kill the cell (not really what you want in someone who does not have a lot of T-cells), but its enough to keep the HIV-1 that got into the cell from making any baby viruses.

Wat?

WAT??

:-/

Thats awesome!

I mean, this still has all of the problems inherent in gene-therapy/bone-marrow transplants/etc– but Im much more excited about a general ‘anti-HIV’ strategy like this than the others that have been proposed thus far (which might only be very solvable problems, to a quasispecies).

Related

Comments

Long time lurker, first time commenter. I can’t seem to be able to get access to the paper through my university.
Although I thought this was done before. If not, in hindsight, it is simple to see how this could have been thought of. Two questions:
1) Are you aware of any other putative HIV therapies/control mechanisms that use bacteria (whole or otherwise)?
2) Do the authors (or you) know of any mechanism whereby the Tat protein would not evolve specificity for the HIV-1 promoter but not the HIV-2 promoter?

I finally read about quasi-species, but I don’t understand why researchers can’t collect samples from lots of people, sequence the virus genomes to characterize the variations that exist, and then make vaccines for a subset of those viruses spread across the quasi-species. Then if people with the vaccine still get infected, collect samples of the virus from them, and do the same thing to find what’s slipping through the cracks.